A systematic review and dose–response meta-analysis of prospective cohort studies on coffee consumption and risk of lung cancer

Studies on the association between coffee consumption and risk of lung cancer have been conflicting. The aim of this study was to systematically review the current evidence on the association between coffee consumption and risk of lung cancer and to quantify this association by performing a meta-analysis. A comprehensive systematic search was performed on online databases up to July 2023 investigating the association between coffee consumption and risk of lung cancer. All prospective cohort studies reporting odds ratios (ORs), rate or risk ratios (RRs), or hazard ratios (HRs) and 95% confidence intervals (CIs) in this context were included. The overall effect size was calculated using the random-effects model and statistical between-studies heterogeneity was examined using Cochrane’s Q test and I2. A total of 14 prospective cohort studies were included in this systematic review and meta-analysis. We found a significant positive association between coffee consumption and risk of lung cancer (RR: 1.28; 95% CI: 1.12, 1.47). This association remained significant when we included a pooled analysis paper and excluded 5 cohort studies (RR: 1.37; 95% CI: 1.12, 1.66). We observed no proof of significant publication bias using Egger’s test (P = 0.58). Moreover, dose–response analysis showed that each one cup/day increase in coffee consumption was related with a 6% higher lung cancer risk (RR: 1.06; 95% CI: 1.03, 1.09). In conclusion, we found a significant positive association between coffee consumption and risk of lung cancer.


Data extraction
Two reviewers (MJ and ASM) independently extracted the following data from eligible studies: first author's last name, year of publication, cohort name/country, mean age or age range (years), sex, number of subjects, number of cases, follow up duration (years), exposure assessment, outcome assessment, comparison, fully adjusted effect size (ORs, RRs, or HRs) with the corresponding 95% CIs, adjustments, and study quality score.Characteristics of included studies in this systematic review and dose-response meta-analysis are provided in Table 1.

Quality assessment
The quality of studies included in this systematic review and meta-analysis was examined by the Newcastle-Ottawa Scale (NOS).Based on this method, a maximum of nine scores can be awarded to each study.In our analysis, we considered scores of ≥ 6 as high-quality studies, otherwise, the study was deemed to have low quality.Table 1 indicates the results of the quality assessment of the eligible cohorts.

Statistical analysis
All reported ORs, RRs, and HRs and their 95% CIs for risk of lung cancer were used to calculate the log RRs and their SEs.The overall effect size was calculated using the random-effects model, which incorporates betweenstudy heterogeneity.Statistical between-studies heterogeneity was examined using Cochrane's Q test and I-squared (I 2 ).Publication bias was assessed by visual inspection of funnel plots.Formal statistical assessment of funnel plot asymmetry was carried out with Egger's regression asymmetry tests.Sensitivity analysis was used to explore the extent to which inferences might depend on a particular study or group of studies.Statistical analyses were made with Stata MP, version 14. P-values < 0.05 were considered statistically significant.To perform a dose-response analysis, we used studies that reported sufficient information.Studies were considered eligible if they reported the range or median/mean dose of coffee consumption (cups per day), the numbers of cases and participants/person-years, adjusted RRs and their 95% CIs across categories of coffee consumption.We divided the total number of cases, participants, and person-years by the number of categories if a study had not reported the sufficient information in each category.The linear dose-response association was measured using generalized least squares trend estimation, based upon the work of Greenland and colleagues 25,26 .The RR was calculated for a daily increase of one cup of coffee intake in each study.To pool the results of each study, a random-effects model was used.Restricted cubic splines with 3 knots according to Harrell's recommended percentiles of distribution (10th, 50th, and 90th) were used to examine the potential nonlinear association 27 .The null hypothesis was tested by calculating a P-value for non-linearity of the meta-analysis.The test was conducted to check if the coefficient of the second spline was equal to 0.

Results
Letters, reviews, meta-analyses, comments, animal studies, and ecological studies were excluded in the current systematic review and meta-analysis.Following our initial search, 19,389 articles were identified.After removing 1293 duplicates, 18,096 reports remained for further assessment.After title and abstract careful checking and review, 18,076 articles were excluded and 20 publications remained for full-text assessment.Five studies were excluded due to the following reasons: two studies had reported lung cancer mortality 23,24 .In addition, one thesis 28 and two Mendelian studies 29,30 were also excluded.Finally, a total of 14 prospective cohort studies [15][16][17][18][19][20][21][22][31][32][33][34][35][36] and one pooled analysis 37 were included in this systematic review and meta-analysis. Figure illustrates the study selection process.
A recent pooled analysis by Zhu et al. 37 included 17 cohort studies; however, 12 of them were unpublished data with no available full-texts.Therefore, we decided to analyze data once by including the study by Zhu et al. 37 and excluding the 5 studies 17,20,21,31,32 that overlapped with the Zhu et al., and once again by adding the 5 studies and excluding the study of Zhu et al. for better understanding of the association.
Narita et al. 17 had reported effect sizes separately for men and women, however, we combined these two effect sizes and then, included in our analysis.Three studies had not reported the 95% CIs for the association between coffee consumption and risk of lung cancer [34][35][36] .Therefore, we derived relevant data for these studies from the previous meta-analysis 14 .

Findings from the meta-analysis
First, we examined the association by including data from 9 cohort studies not included in the pooled analysis paper of Zhu et al. along with the findings from the pooled analysis.The overall effect size based on these 10 studies 15,16,18,19,22,[33][34][35][36][37] revealed a statistically significant association between coffee consumption and risk of lung cancer (RR: 1.37; 95% CI: 1.12, 1.66; Fig. 2).
Records identified through database searching (n=19,389) Full-text articles assessed for eligibility (n=20) Studies included in systematic review and metaanalysis (n=15)  www.nature.com/scientificreports/ We also found an evidence of statistically significant between-study heterogeneity (I 2 = 76.9%,P < 0.001).No evidence of publication bias was seen (P = 0.93).
However, a significant between-study heterogeneity was found (I 2 = 69.5%,P < 0.001).A sensitivity analysis showed that no particular study had a significant influence on the summary effects.In addition, we observed no proof of significant publication bias using Egger's test (P = 0.58).(Funnel plot has provided as Supplementary Fig. 1).
To find sources of heterogeneity, we performed subgroup analyses based on fixed-effects model.In the subgroup analyses, we found that sex, follow-up duration, and country might explain between-study heterogeneity (Table 2).
A total of 3 studies were excluded from dose-response analysis as they did not provide sufficient information even after receiving two email requests 19,20,35 .Therefore, 11 studies remained for further analyses.Results from 8 studies including Zhu et al. study demonstrated that each one cup/day increase in coffee consumption was associated with a 6% higher risk of lung cancer (RR: 1.06; 95% CI: 1.03, 1.09; Fig. 4).
The risk of lung cancer increased linearly with coffee consumption of approximately 1-5 cups per day in a nonlinear dose-response analysis (P nonlinearity: 0.94; P dose-response: 0.001; Fig. 5).
Such associations were observed when we excluded the study of Zhu et al. and included 11 cohort studies in the linear dose-response analysis (RR: 1.06; 95% CI: 1.03, 1.08, P nonlinearity = 0.65; Fig. 6).
There was also a linear association between coffee consumption and risk of lung cancer (P nonlinearity = 0.94, P dose-response: 0.001; Fig. 7).

Discussion
This systematic review and meta-analysis on 14 prospective cohort studies and a pooled analysis indicated a significant positive association between coffee consumption and risk of lung cancer.It was also found that an increase of one cup of coffee per day was linked to a higher risk of lung cancer, according to the dose-response analysis.To the best of our knowledge, this is the most comprehensive and updated meta-analysis about coffee consumption and risk of lung cancer.
Lung cancer imposes a great burden on the health care system.Although smoking is a well-established risk factor for this condition, dietary factors also play an important role.Fruit and vegetables consumption was  inversely associated with risk of lung cancer in earlier studies 38 .In addition, consumption of American/Western dietary pattern has been associated with 45% elevated risk of lung cancer 39 .Coffee is a regular drink in most parts of the world and evaluating its contribution to human health is of high importance.We found that coffee consumption was associated with a greater risk of lung cancer.Such findings were also reported from a metaanalysis on 5 cohort studies in 2010 13 and a meta-analysis on 8 cohort studies in 2016 14 .Another previous metaanalysis conducted in 2016 also indicated a significant positive association between coffee consumption and risk of lung cancer 11 .Data from a prospective cohort study on Women's Health Initiative (WHI) observational study reported a significant elevated risk of lung cancer for regular, decaffeinated, and total coffee consumption 28 .In contrast to our findings, a meta-analysis on 8 case-control studies revealed no significant association between coffee consumption and risk of lung cancer 13 .In addition, a case-control study reported a significant inverse association between weekly compared to never coffee consumption and risk of lung cancer 40 .In the meta-analysis  published in 2016, when the authors combined prospective cohort and case-control studies, without controlling for smoking, a significant association was seen between coffee consumption and risk of lung cancer; however, after restricting the analysis to studies that adjusted for smoking, no significant association was observed 14 .
The discrepant findings can be explained by the difference in the number of studies included in different metaanalyses.In addition, combining effect sizes from case-control studies with those from prospective cohort studies would result in misleading findings.We included a total of 14 cohort studies in the current analysis with a total population of 1,061,854 people and 19,643 incident cases of lung cancer [15][16][17][18][19][20][21][22][31][32][33][34][35][36] . Comparng these figures with the numbers in previous meta-analyses, it is clear that we had a larger number of people and incident cases in the current analysis, which make our findings more valid and reliable.
The mechanisms through which coffee consumption might affect the risk of lung cancer still remain to be identified.Some biochemically active components of coffee might influence cancer risk.Coffee can be an important dietary source of acrylamide which is a genotoxic agent.Roasting process helps increasing acrylamide content of coffee 41 .Acrylamide can cause DNA damage in mammalian tissues and induce oxidative stress and thus trigger cancer cell formation 42 .Caffeine is a widely known substance in coffee which might have mutagenic effect on cancer development 43 .However, some studies have also reported anti-cancer properties for caffeine 44 .Despite these contents of coffee, it might also have cancer-protective effects.Cafestol and Kahweol may potentially inhibit tumor growth by blocking or diminishing neoangiogenesis, however, they also increase cardiovascular risk by raising the concentration of serum lipids 45 .Overall, it seems that coffee with its ingredients might be beneficial or detrimental to different cancers and further studies are needed to elucidate the relevant mechanisms.
Our study has several strengths.Restricting the analysis to prospective cohort studies as well as large number of included studies and participants compared to previous ones are among several strengths.In addition, findings from a recent pooled analysis were also used carefully without overlapping the included studies.This has been resulted to include a large number of individuals in the analysis, in particular from cohort studies for which there are no original report about coffee consumption and lung cancer.However, some limitations must be noted when interpreting our results.This systematic review and meta-analysis was performed based on observational studies with their inherent limitations.Therefore, it is difficult to make a conclusive decision about the causal association between coffee consumption and risk of lung cancer.In addition, for most included studies, coffee consumption was assessed using a food frequency questionnaire.Therefore, measurement error and misclassification of study participants in terms of exposure were unavoidable.Both non-differential misclassification and measurement errors attenuate the relative risk.Furthermore, the present systematic review and meta-analysis included studies that had enrolled subjects from different countries with different dietary habits and racial factors, which could be associated with different risks of lung cancer.Despite adjustment for several potential confounders in primary studies, the possibility of residual confounding cannot be ignored.The quality of the included studies and generalizability of the results should also be noted.Finally, we were unable to examine the association between different types of coffee and risk of lung cancer, because included studies had not reported such information separately.
In conclusion, this systematic review and meta-analysis indicated a significant positive association between coffee consumption and risk of lung cancer.Further studies, especially with prospective design, are required to expand our knowledge on the association between coffee consumption and risk of lung cancer.

Figure 1 .
Figure 1.Flowchart of the study selection process.

Figure 4 .
Figure 4. Relative risk of lung cancer for a one cup/day increment in coffee consumption based on 8 studies.

Figure 5 .
Figure 5. Nonlinear dose-response association between coffee consumption and the risk of lung cancer (P non-linearity = 0.82) based on 8 studies.

Figure 6 .
Figure 6.Relative risk of lung cancer for a one cup/day increment in coffee consumption based on 11 studies.

Figure 7 .
Figure 7. Nonlinear dose-response association between coffee consumption and risk of lung cancer based on 11 studies.

Table 2 .
Subgroup analyses for the association between coffee consumption and risk of lung cancer.CI confidence interval, RR rate or risk ratio, FFQ food frequency questionnaire.